Clinical Trials Experience

Because clinical studies are conducted under widely
varying and controlled conditions, adverse reaction rates observed in clinical
studies of a drug cannot be directly compared to rates in the clinical studies
of another drug, and may not predict the rates observed in a broader patient
population in clinical practice.

Adverse Reactions Most Commonly Leading to
Discontinuation of Treatment in Premarketing Controlled Trials

The proportion of patients with Crohn's disease who
discontinued treatment due to adverse reactions in the controlled clinical
studies was 8% for CIMZIA and 7% for placebo. The most common adverse reactions
leading to the discontinuation of CIMZIA (for at least 2 patients and with a
higher incidence than placebo) were abdominal pain (0.4% CIMZIA, 0.2% placebo),
diarrhea (0.4% CIMZIA, 0% placebo), and intestinal obstruction (0.4% CIMZIA, 0%
placebo).

The proportion of patients with rheumatoid arthritis who
discontinued treatment due to adverse reactions in the controlled clinical
studies was 5% for CIMZIA and 2.5% for placebo. The most common adverse
reactions leading to discontinuation of CIMZIA were tuberculosis infections
(0.5%); and pyrexia, urticaria, pneumonia, and rash (0.3%).

Controlled Studies with Crohn's Disease

The data described below reflect exposure to CIMZIA at
400 mg subcutaneous dosing in studies of patients with Crohn's disease. In the
safety population in controlled studies, a total of 620 patients with Crohn's
disease received CIMZIA at a dose of 400 mg, and 614 subjects received placebo
(including subjects randomized to placebo in Study CD2 following open label
dosing of CIMZIA at Weeks 0, 2, 4). In controlled and uncontrolled studies,
1,564 patients received CIMZIA at some dose level, of whom 1,350 patients
received 400 mg CIMZIA. Approximately 55% of subjects were female, 45% were
male, and 94% were Caucasian. The majority of patients in the active group were
between the ages of 18 and 64. During controlled clinical studies, the
proportion of patients with serious adverse reactions was 10% for CIMZIA and 9%
for placebo. The most common adverse reactions (occurring in ≥ 5% of

Other Adverse Reactions

The most commonly occurring adverse reactions in
controlled trials of Crohn's disease were described above. Other serious or
significant adverse reactions reported in controlled and uncontrolled studies
in Crohn's disease and other diseases, occurring in patients receiving CIMZIA
at doses of 400 mg or other doses include:

Controlled Studies with Rheumatoid Arthritis

CIMZIA was studied primarily in placebo-controlled trials
and in long-term follow-up studies. The data described below reflect the
exposure to CIMZIA in 2,367 RA patients, including 2,030 exposed for at least 6
months, 1,663 exposed for at least one year and 282 for at least 2 years; and
1,774 in adequate and well-controlled studies. In placebo-controlled studies,
the population had a median age of 53 years at entry; approximately 80% were
females, 93% were Caucasian and all patients were suffering from active
rheumatoid arthritis, with a median disease duration of 6.2 years. Most
patients received the recommended dose of CIMZIA or higher.

Table 1 summarizes the reactions reported at a rate of at
least 3% in patients treated with CIMZIA 200 mg every other week compared to
placebo (saline formulation), given concomitantly with methotrexate.

Table 1: Adverse Reactions Reported by ≥ 3% of
Patients Treated with CIMZIA Dosed Every Other Week during Placebo-Controlled
Period of Rheumatoid Arthritis Studies, with Concomitant Methotrexate.

Adverse Reaction (Preferred Term)

Placebo+ MTX# (%)
N =324

CIMZIA 200 mg EOW + MTX(%)
N =640

Upper respiratory tract infection

2

6

Headache

4

5

Hypertension

2

5

Nasopharyngitis

1

5

Back pain

1

4

Pyrexia

2

3

Pharyngitis

1

3

Rash

1

3

Acute bronchitis

1

3

Fatigue

2

3

#EOW = Every other Week, MTX = Methotrexate.

Hypertensive adverse reactions
were observed more frequently in patients receiving CIMZIA than in controls.
These adverse reactions occurred more frequently among patients with a baseline
history of hypertension and among patients receiving concomitant
corticosteroids and non-steroidal anti-inflammatory drugs.

Patients receiving CIMZIA 400
mg as monotherapy every 4 weeks in rheumatoid arthritis controlled clinical
trials had similar adverse reactions to those patients receiving CIMZIA 200 mg
every other week.

Other Adverse Reactions

Other infrequent adverse
reactions (occurring in less than 3% of RA patients) were similar to those seen
in Crohn's disease patients.

Psoriatic Arthritis Clinical
Study

CIMZIA has been studied in 409
patients with psoriatic arthritis (PsA) in a placebo-controlled trial. The
safety profile for patients with PsA treated with CIMZIA was similar to the
safety profile seen in patients with RA and previous experience with CIMZIA.

Infections

The incidence of infections in
controlled studies in Crohn's disease was 38% for CIMZIA-treated patients and
30% for placebo-treated patients. The infections consisted primarily of upper
respiratory infections (20% for CIMZIA, 13% for placebo). The incidence of
serious infections during the controlled clinical studies was 3% per
patient-year for CIMZIA-treated patients and 1% for placebo-treated patients.
Serious infections observed included bacterial and viral infections, pneumonia,
and pyelonephritis.

The incidence of new cases of
infections in controlled clinical studies in rheumatoid arthritis was 0.91 per
patient-year for all CIMZIA-treated patients and 0.72 per patient-year for
placebo-treated patients. The infections consisted primarily of upper respiratory
tract infections, herpes infections, urinary tract infections, and lower
respiratory tract infections. In the controlled rheumatoid arthritis studies,
there were more new cases of serious infection adverse reactions in the CIMZIA
treatment groups, compared to the placebo groups (0.06 per patient-year for all
CIMZIA doses vs. 0.02 per patient-year for placebo). Rates of serious
infections in the 200 mg every other week dose group were 0.06 per patient-year
and in the 400 mg every 4 weeks dose group were 0.04 per patient-year. Serious
infections included tuberculosis, pneumonia, cellulitis, and pyelonephritis. In
the placebo group, no serious infection occurred in more than one subject.
There is no evidence of increased risk of infections with continued exposure
over time [see WARNINGS AND PRECAUTIONS].

Tuberculosis and Opportunistic
Infections

In completed and ongoing global
clinical studies in all indications including 5,118 CIMZIA-treated patients,
the overall rate of tuberculosis is approximately 0.61 per 100 patient-years
across all indications.

The majority of cases occurred
in countries with high endemic rates of TB. Reports include cases of miliary,
lymphatic, peritoneal, as well as pulmonary TB. The median time to onset of TB
for all patients exposed to CIMZIA across all indications was 345 days. In the
studies with CIMZIA in RA, there were 36 cases of TB among 2,367 exposed
patients, including some fatal cases. Rare cases of opportunistic infections
have also been reported in these clinical trials. [see WARNINGS AND
PRECAUTIONS].

Malignancies

In clinical studies of CIMZIA,
the overall incidence rate of malignancies was similar for CIMZIA-treated and
control patients. For some TNF blockers, more cases of malignancies have been
observed among patients receiving those TNF blockers compared to control
patients. [see WARNINGS AND PRECAUTIONS]

Heart Failure

In placebo-controlled and open-label rheumatoid arthritis
studies, cases of new or worsening heart failure have been reported for
CIMZIA-treated patients. The majority of these cases were mild to moderate and
occurred during the first year of exposure. [see WARNINGS AND PRECAUTIONS].

Autoantibodies

In clinical studies in Crohn's disease, 4% of patients
treated with CIMZIA and 2% of patients treated with placebo that had negative
baseline ANA titers developed positive titers during the studies. One of the
1,564 Crohn's disease patients treated with CIMZIA developed symptoms of a
lupus-like syndrome.

In clinical trials of TNF blockers, including CIMZIA, in
patients with RA, some patients have developed ANA. Four patients out of 2,367
patients treated with CIMZIA in RA clinical studies developed clinical signs
suggestive of a lupus-like syndrome. The impact of long-term treatment with
CIMZIA on the development of autoimmune diseases is unknown [see WARNINGS
AND PRECAUTIONS].

Immunogenicity

Patients were tested at multiple time points for
antibodies to certolizumab pegol during Studies CD1 and CD2. The overall
percentage of antibody positive patients was 8% in patients continuously
exposed to CIMZIA, approximately 6% were neutralizing in vitro. No apparent
correlation of antibody development to adverse events or efficacy was observed.
Patients treated with concomitant immunosuppressants had a lower rate of
antibody development than patients not taking immunosuppressants at baseline
(3% and 11%, respectively). The following adverse events were reported in
Crohn's disease patients who were antibody-positive (N = 100) at an incidence
at least 3% higher compared to antibody-negative patients (N = 1,242):
abdominal pain, arthralgia, edema peripheral, erythema nodosum, injection site
erythema, injection site pain, pain in extremity, and upper respiratory tract
infection.

The overall percentage of patients with antibodies to
certolizumab pegol detectable on at least one occasion was 7% (105 of 1,509) in
the rheumatoid arthritis placebo-controlled trials. Approximately one third
(3%, 39 of 1,509) of these patients had antibodies with neutralizing activity in
vitro. Patients treated with concomitant immunosuppressants (MTX) had a lower
rate of antibody development than patients not taking immunosuppressants at
baseline. Patients treated with concomitant immunosuppressant therapy (MTX) in
RA-I, RA-II, RA-III had a lower rate of neutralizing antibody formation overall
than patients treated with CIMZIA monotherapy in RA-IV (2% vs. 8%). Both the
loading dose of 400 mg every other week at Weeks 0, 2 and 4 and concomitant use
of MTX were associated with reduced immunogenicity.

Antibody formation was associated with lowered drug
plasma concentration and reduced efficacy. In patients receiving the
recommended CIMZIA dosage of 200 mg every other week with concomitant MTX, the
ACR20 response was lower among antibody positive patients than among
antibody-negative patients (Study RA-I, 48% versus 60%; Study RA-II 35% versus
59%, respectively). In Study RA-III, too few patients developed antibodies to
allow for meaningful analysis of ACR20 response by antibody status. In Study
RA-IV (monotherapy), the ACR20 response was 33% versus 56%, antibody-positive
versus antibody-negative status, respectively. [see CLINICAL PHARMACOLOGY].
No association was seen between antibody development and the development of
adverse events.

The data reflect the percentage of patients whose test
results were considered positive for antibodies to certolizumab pegol in an
ELISA, and are highly dependent on the sensitivity and specificity of the
assay. The observed incidence of antibody (including neutralizing antibody)
positivity in an assay is highly dependent on several factors, including assay
sensitivity and specificity, assay methodology, sample handling, timing of
sample collection, concomitant medications, and underlying disease. For these
reasons, comparison of the incidence of antibodies to certolizumab pegol with
the incidence of antibodies to other products may be misleading.

Hypersensitivity Reactions

The following symptoms that could be compatible with
hypersensitivity reactions have been reported rarely following CIMZIA
administration to patients: angioedema, dermatitis allergic, dizziness
(postural), dyspnea, hot flush, hypotension, injection site reactions, malaise,
pyrexia, rash, serum sickness, and (vasovagal) syncope [see WARNINGS AND
PRECAUTIONS].

Postmarketing Experience

The following adverse reactions have been identified
during post-approval use of CIMZIA. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible to
estimate reliably their frequency or establish a causal relationship to drug
exposure.

Vascular disorder: systemic vasculitis has been
identified during post-approval use of TNF blockers.

Skin: case of severe skin reactions, including
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and
new or worsening psoriasis (all sub-types including pustular and palmoplantar)
have been identified during post-approval use of TNF blockers.

DRUG INTERACTIONS

Use with Anakinra, Abatacept, Rituximab, and Natalizumab

An increased risk of serious infections has been seen in
clinical studies of other TNF-blocking agents used in combination with anakinra
or abatacept, with no added benefit. Formal drug interaction studies have not
been performed with rituximab or natalizumab. Because of the nature of the
adverse events seen with these combinations with TNF blocker therapy, similar
toxicities may also result from the use of CIMZIA in these combinations. There
is not enough information to assess the safety and efficacy of such combination
therapy. Therefore, the use of CIMZIA in combination with anakinra, abatacept,
rituximab, or natalizumab is not recommended [see WARNINGS AND PRECAUTIONS].

Live Vaccines

Laboratory Tests

Interference with certain coagulation assays has been
detected in patients treated with CIMZIA. Certolizumab pegol may cause
erroneously elevated activated partial thromboplastin time (aPTT) assay results
in patients without coagulation abnormalities. This effect has been observed
with the PTT-Lupus Anticoagulant (LA) test and Standard Target Activated
Partial Thromboplastin time (STA-PTT) Automate tests from Diagnostica Stago,
and the HemosIL APTT-SP liquid and HemosIL lyophilized silica tests from
Instrumentation Laboratories. Other aPTT assays may be affected as well.
Interference with thrombin time (TT) and prothrombin time (PT) assays has not
been observed. There is no evidence that CIMZIA therapy has an effect on in
vivo coagulation.